Radiotherapy and Oncology, 19 (1990) 137-144 Elsevier
137
RADION 00769
Intraoperative plus external beam irradiation in nonresectable lung cancer: assessment of local response and therapy-related side effects Karin S. Arian-Schad I, Freyja M. Juettner 2, Beatrix Ratzenhofer 3, Hubert Leitner ‘, Guenter Porsch I, Hans Pinter *, Franz Ebner I, Arnulf G. Hack1 ’ and Gerhard B. Friehs * University Clinic of Radiology.
’Division of Radiotherapy, Departments of 2 Thoracic and Hyperbaric Surgery, and 3 Department of Anesthesiology, University Medical School Graz, Graz, Austria
(Received 8 January 1990, revision received 3 May 1990, accepted 10 May 1990)
Ke_Jawords
: Intraoperative radiation; External beam therapy; Lung cancer
Summary
(NSCLC), stage T,_, N,_, M,, have undergone lymph node dissection and intraoperative radiation therapy (IORT) to the primary with Since
1987, 24 patients
with inoperable
non-small-cell
lung cancer
lo-20 Gy. Patient selection criteria were nonresectability based on severe cardiorespiratory impairment, no radiological evidence of distant metastases and a Karnofsky performance status of > 80. In 18 patients the IORT procedure was followed by an external beam radiation series (EBR) including the tumor with 46 Gy and the regional lymph nodes with 46/56 Gy. The tumor response was assessed by CAT-scan volumetry before the institution of IORT, 4 weeks later, before the onset of EBR, 8 weeks after the combined treatment course and on a 3 months basis thereafter. Prospectively, MRI of the thorax with/without Gadolinium-DTPA was performed to examine contrast enhancement and signal behavior of the tumor, in an attempt to differentiate residual disease compared to therapy-related collateral damage. So far, 18 patients have completed the combined treatment course with a median follow-up of 11 months (range 4.5 to 25 months). The overall local response rate (CR and PR) was 88.2%. In detail, 11 complete responses, 6 partial responses and one minimal response were observed. The overall and recurrence-free survival at 25 months was 49.6% and 83.3%, respectively.
Introduction Cancer of the lung is the leading cause of death in the male population in the western industrial Address for correspondence
: Karin S. Arian-Schad, UniverClinic of Radiology, Division of Radiotherapy, Auenbruggerplatz 9, A-8036 Graz, Austria. sity
world. Although radical surgery offers a good chance for cure in limited stage of disease [ 10,21-23,311, 70% of patients will be found unsuitable for oneration at time of diagnosis [ 9,22,23]. Due td either severe cardioresp;atory impairment, which surgical procedure,
0167-8140/90/$03.50 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
does not allow an extensive or to anatomical unresecta-
138 bility and/or distant spread, these patients ultimately might be considered to receive radiation treatment during their course of disease [9,16,24,26]. Various doses of radiation and fractionation schedules have been used in patients with bronchogenic carcinoma [ 16,19,26,30]. Several studies have indicated, that the probability of local control depends on the total dose delivered, but even with high doses, up to 44% of patients showed failure at the initial site of the tumor. Only patients in whom local control had been achieved had a prolonged survival [26,30]. Sensitive structures and normal lung parenchyma within the treatment field restrict further increase in dosage in spite of sophisticated treatment planning methods. This is particulary relevant in patients, in whom cardiopulmonary dysfunction is the cause for inoperability, or in patients, in whom large portals would be required to encompass the lesion and the regional area of lymphatic spread
We did a controlled study, applying IORT in combination with postoperative EBR in a collective of functionally nonresectable patients, who otherwise would have been candidates for conventional EBR only. In order to assess the treatment response and possible side effects in this patient series, short term follow-up examinations with CAT-scan were scheduled. As the study was ongoing, native and contrast MRI was used in addition to obtain further information in differentiating collateral damage and tumor regression.
Patients and methods Between October 1987 and November 1989, 24 patients (3 females, 2 1 males), aged 5 l-80 years (mean: 65 years) were treated with IORT to the unresected primary. Treatment selection criteria included patients with histopathologically or cytologically confirmed diagnosis of non-small-cell
[121. Intraoperative radiation therapy (IORT) has demonstrated to be a feasible approach for tumors, in which, due to their topographical location, doses necessary for local control cannot be delivered safely by external treatment alone [l-4,1 1,15,18,27,28]. In addition, IORT has been demonstrated to be an attractive boosting modality in conjunction with surgery and/or conventional external beam radiation for a variety of tumors [3,6,11,13-14,271. The clinical experience of IORT in lung cancer is still limited [ 1,4,5,7,11,25]. Several experimental studies have evaluated the tolerance of mediastinal structures and/or lung tissue to large single dose radiation delivered intraoperatively :[ 8,25,29]. Information on lung tolerance to external beam radiation (EBR) given in addition to IORT is scarce [ 71. No data exist concerning acute or late tissue reactions following a combined IORT/EBR approach or on the difficulties encountered in obtaining follow-up evaluation, which can differentiate residual disease from marked fibrosis related to normal tissue damage.
TABLE
I
Patient pretreatment
characteristics.
No. of patients Tumor stage (AJC) T,
24 7
T,
10
T,
7
Lymph node involvement NO
15
N,
2
N*
7
Histologic subtype
Squamous Adeno Large cell
14 6 4
Tumor grading
Moderately differentiated Poorly differentiated
13 11
Localisation
Left upper lobe Left lower lobe Right upper lobe Right lower lobe
6 5 4 9
139 lung cancer (NSCLC), stage T,_, N,_, (AJC staging criteria 1988) and no radiological evidence of distant metastases (Table I). Only cases, who were considered inoperable because of severe cardiopulmonary impairment with a Karnofsky performance status of > 80 entered this protocol. Pretreatment evaluation included history, physical examination, blood chemistries, chest X-ray, CT and MRI of the thorax, fibrebronchoscopy and cardiorespiratory function tests (spirometry, ventilation-perfusion body-plethysmography, exercise electrocardiogram, scan, ergometry, ultrasound cardiography). In addition, bone scan and ultrasound of the abdomen were performed to help rule out distant metastases. Prospectively, an external photon beam series (8 MeV) to the tumor with 46 Gy and the regional lymph nodes with 46/56 Gy was scheduled 4 weeks after IORT with curative intention. Surgical technique and IORT Surgery is performed inside the radiation therapy room under sterile conditions. The tumor is exposed by a posterolateral thoracotomy and a biopsy is taken by pulmotomy in cases in whom only cytological diagnosis had been obtained. Lymph node dissection in the respective drainage area, following the standard procedure otherwise combined with resection, is done for staging purposes. Both the tumor biopsy and the dissected lymph nodes are examined intraoperatively by frozen section histology before IORT is initiated. Because of the poor cardiorespiratory function in our collective, IORT had to be delivered with the tumor-bearing lung partially ventilated. This technique provided both satisfactory ventilation and sufficient mobility of tumor-bearing lung at its hilum which is necessary for an optimum positioning of the cone. Dependent on the tumor size of the primary a lucite sterile cone of appropriate diameter is firmly put over the lesion with a macroscopically tumorfree margin of 1.5 cm. Doses between 10 and 20 Gy, with electron energies in the range of 11 to 20 MeV are applied to ensure homogeneous dose
TABLE
II
IORT treatment
data of 24 patients
IORT tumor dosage (Gy) (90 % isodose) 10
15 11 20
1 2 1 20
Electron beam energy (MeV) I
1
11
6
15
13
20
4
Cone diameter (cm) 4
1
6
12
8
6
10
5
distribution within the treatment volume (Table II). Dose-limiting structures are simultaneously shielded. by 2 cm thick aluminum blocks, which are positioned between the tumor and underlying or adjacent normal tissue. This is to ensure additional protection of structures known for sensitivity, such as esophagus, trachea, heart, spinal cord and big vessels. The IORT set-up, consisting of straight and beveled cones with diameters of 4- 10 cm, and the adaptor system with a secondary collimator connected to the accelerator head, are both selfdeveloped [20]. Since calibration of the accelerator beam is done on a day to day basis, the dose calculation data for the various cone diameters and energies prescribed to the 90% iso-dose, are listed in a table and thus allow quick determination of dosimetry parameters. Special protocol forms are used for documentation of clinical and physical data of the IORT procedure. External beam radiation Four weeks after IORT an external photon beam (8 MeV) radiation series with conventional fractionation (2 Gy/day, 5 times a week) is initiated. Treatment is planned with a CT-aided
140 computer planning system with dose calculation in at least three section planes. Radiation is delivered through individually shaped divergent cerrobend blocks using AP/PA fields and additional lateral fields in patients with left lower lobe tumors, in order to reduce the dosage to the heart. A total dose of 46 Gy is applied to the tumor and the regional lymph node area. In patients with histopathologically confirmed lymph node involvement an additional electron boost to the mediastinum is added to increase the total dose up to 56 Gy. For the mediastinal boost electron energies of either 20 or 25 MeV are used in order to ensure a homogeneous dose distribution in the target volume. For an optimum delivery precluding damage to the spinal cord, computerized treatment planning is performed in each case. Radiologicalfollow-up Follow-up consisted of CAT-scan volumetry of the tumor preoperatively, 4 weeks after IORT, 8 weeks after IORT and EBR, and on a 3 months basis thereafter. Additional 4 mm scans in a high resolution mode were performed, to assess possible interstitial changes of the lung parenchyma within the intraoperative treatment port. Since 1988, MRI with and without Gadolinium-DTPA contrast medium has been utilized to examine the contrast behavior of the tumor before and after radiation therapy. Patients were examined with a 1.5 Tesla Gyroscan (Tlweighted spin-echo sequences, repetition times of 550-750 ms, echo times 25-30 ms) in at least two planes, followed by contrast scans after intravenous injection of 0.1 mmol Gd-DTPA/kg.
Results Eighteen of 24 patients have so far undergone the combined IORT/EBR approach and are available for evaluation of tumor response (Fig. 1) with a median follow-up time of 11 months (range 4.5 to 26 months).
Volume
of turnour (am31
Patients ranked according to intial vol. 0
VoIum*try
4
es
VOIUm*try
vohJm*try
1
I
Pr*alr*atm.
Volunntry
3
2
Volum*
Fig. 1. Pre- and post-therapeutic tumor volume measurements in 18 patients treated with IORT and EBR.
The first follow-up volumetry, 4 weeks after IORT, revealed 9 minimal responses (MR, tumor regression 50%), and one complete response (CR). In one patient volume regression could not be assessed due to marked surgically and/or radiation-induced artefacts. At second CAT-scan volumetry, 18 weeks alter IORT, 5 CR, 11 PR and 1 MR were observed, respectively. One patient was lost with a lethal intrabronchial bleeding during his course of EBR. As follow-up time reached 30-46 weeks, volume measurements were hampered by increasing tissue reactions. Furthermore, differentiation of fibrosis versus possible residual disease by CT was not reliable due to similar attenuation values of both tissues. At that time, MRI, which had been prospectively scheduled in 12 patients, seemed helpful in discerning surgically and radiation-induced parenchymal damage versus residual disease or tumor regrowth. Pleural thickening could be clearly delineated in 7/12, partial or total atelectasis in 4/12 and fibrosis in lo/12 patients, showing homogeneous signal behavior patterns with/without application of contrast medium. These findings were in contrast to focal Gd-DTPA enhancement, suspicious for residual disease, within areas of consolidation in two patients, of whom in one subsequent local
141 IORT in NSCLC (N=lS) Overall and recurrence-free
survival
20:
OrA
3
7
10 11
15
25
months -
OvBrallw.
-
recurrencstree 8”.
Fig. 2. Overall and recurrence-free EBR.
survival after IORT and
progression occurred 12 months after IORT. In one case an ipsi- and contralateral lung metastasis, both located outside the radiation ports, were diagnosed by CT and MRI, presenting with identical Gd-DTPA contrast enhancement as compared to the primary lesion before initiation of therapy. Six patients died, of which 4 succumbed to their pre-existent cardiac insulhciency 6, 12, 14 and 15 months alter IORT, including 2 patients with complete tumor regression. Only in one patient local tumor regrowth occurred with subsequent distant spread in his later course of disease. One patient died of acute intrabronchial hemorrhage while undergoing EBR. Based on both MRI findings and CT volumetries at the most recent follow-up according to the agreed schedule, an overall local control rate of 88.2% was achieved, including 11 CR and 6 PR. 16 out of the 18 patients remained without local or distant recurrence during follow-up. The overall and recurrence-free survival (Fig. 2) at 25 months was 49.6% and 83.3x, respectively.
Complications and toxicity The IORT procedure was well tolerated. Postoperative or infectious complications due to thoracotomy and lymph node dissection were not
observed. In one patient with severe bullous emphysema, a prolonged bronchopleural fistula after fine needle aspiration cytology, necessitated an intercostal suction drainage for 10 days. In another case, the hospital stay was prolonged due to cerebrovascular insufficiency. The median duration of hospital care after IORT was 10.7 days. One serious complication, which might have been associated to IORT, occurred in a patient, in whom a cavitating lesion and infiltration into the pulmonary vein had been diagnosed before initiation of therapy. After 50% of tumor regression he died of intrabronchial hemorrhage during his course of EBR. One patient presented with unexplained transient thrombocytopenia (20000 cm3 platelets) 2 weeks after IORT. Paraneoplastic symptoms limited to the skin were observed in three cases, including dermatalgia, pruritus and one erythema multiforme (Table III). These reactions were noted at a median time of 4 months after completion of therapy and affected two patients with clinically complete remission of tumor. Pronounced pneumonitis causing clinical symptoms occurred in five patients, starting 16-18 weeks after IORT, whereas radiological signs of acute parenchymal reactions were observed as early as 4 weeks in one patient and 10 weeks after IORT in two patients. In the remaining cases, however, pneumonitis causing clinical symptoms, was clearly related to marked parenchymal changes within the external radiation ports. The onset and duration of these acute reactions was comparable to acute side
TABLE
III
Complications
and toxicity.
Prolonged fistula after fine needle aspiration cytology Intrabronchial hemorrhage Thrombocytopenia Pneumonitis with clinical symptoms Paraneoplastic pruritus Paraneoplastic dermatalgia Erythema multiforme
1 1 1 5 1 1 1
142 effects associated with EBR alone. An increase in acute lung tissue damage within IORT portals could not be observed, which might have been due to a “miss”, simply by overlapping of IORT and EBR-induced tissue reactions. In all patients the external series could be delivered on an outpatient basis. The common side effects of EBR, such as fatigue, loss of appetite, tracheitis and esophagitis did not seem to be enhanced by the combined treatment regimen. All patients were able to resume their normal life within 2 months after completion of therapy. Late side effects, other than fibrotic changes of varying extent within external treatment portals, could not be observed up to this time.
Discussion The curative role of surgery in technically operable lung cancer is well established [ 10,22,23,3 I]. The comparison of surgical and radiation therapy series, however, remains crucial, since intraoperative staging can hardly be compared to a radiological one, in spite of modern imaging techniques. In recent years, the curative efficacy of aggressive radiotherapy has been investigated and several studies indicated, that increase in dosage yields a higher probability of intrathoracic tumor control and improves survival. In fact, a series by Noordjik et al. [24] reported on a 5-year survival of 42 y0 in a group of primarily irradiated patients with stage T,_, N, M, tumors, who had achieved a complete response to therapy. These results compared favorably to a group of patients, who under the same circumstances were selected for operation. The correlation between dose and objective tumor response has been clearly demonstrated by the RTOG study, with local failure rates of 48% in patients treated with 40 Gy as compared to 27% in those who received 60 Gy continuous course treatment [26]. This study comprised a high percentage of advanced lesions and also showed that doses of 60 Gy still are insufficient for tumors which exceed 6 cm in diameter.
With further increase of dosage, however, irreversible damage to surrounding tissue is to be expected, in spite of shrinking field technique, based upon sophisticated treatment planning. Theoretically, the use of IORT may thus improve the therapeutic ratio between tumor control and normal tissue toxicity, and permits the delivery of adequate tumor doses with maximum sparing of normal lung parenchyma. Some authors, such as Abe et al. [ 1,2] have pointed out that many patients with carcinoma of the lung die with distant metastases, and thus represent poor candidates for IORT. It has to be kept in mind, however, that survival is not a reliable indicator of effectiveness of irradiation in tumors, which are known to have a high tendency for systemic spread and in whom chemotherapy usually fails to alter the course of disease. In absence of distant metastases at initiation of treatment, and in cases of posttherapeutic control of tumor, an improvement of long-term survival can be expected in at least one third of patients. In our protocol, which was primarily inducted for functionally inoperable patients, nine cases turned out be technically unresectable as well. In seven, lymph node dissection revealed involvement of N, nodes, which were resected as radically as possible and treated with 56 Gy external radiation. None of these patients, up to now, has failed in the mediastinum and only one patient with N, nodes has so far developed distant metastases 16 months after treatment alongside local regrowth of the primary. In comparison to other studies [ 16,26,30], the intrathoracic failure rate of 11% at 2 years, including the patient with subsequent developement of intrapulmonary metastases, is comparatively low. The overall local response rate of 88.2% (CR and PR), with 6 1 y0 complete remissions based on CT and MRI evaluation seems promising. Taking into account the poor general medical condition of our patients, which was, after all, the reason for nonresectability, thoracotomy with IORT and EBR was extremely well tolerated. Even though follow-up is limited, the preliminary results with an overall survival (four intercurrent
143 deaths included) of 49.6% and a recurrence-free survival of 83.3%, are encouraging. A local response rate of 80% in 30 patients has been reported by Calvo et al. [7], utilizing a similar treatment approach. In his series, however, IORT was also applied in radically or partially resected lesions and thus cannot be strictly compared to our study. The low complication rate in our patients might be based upon careful avoidance of mediastinal structures into the IORT port, the additional shielding of adjacent sensitive structures and the fact that IORT doses have been limited to lo-20 Gy, depending on tumor size and location. Experimental data by Pass et al. [25] and Barnes et al. [8], as well as early clinical results have demonstrated, that irradiation of mediastinal structures with doses in excess of 20 Gy might result in severe damage and life-threatening symptoms. Goldson [ 111 reported on four cases treated by IORT of the hilum after the primary had been resected. In one patient, who died 6 months after treatment, esophageal stricture was found. The largest series on 5 1 patients with intrathoracic malignancies treated with IORT was reported by Abe et al. [ 21. Detailed data are given in eight patients, of whom only one patient received additional EBR. The median survival time in these patients with far advanced disease was 9 months, with 5 of 8 patients succumbing to their disease within the first year [4]. The Memorial Sloan-Kettering Cancer Center experience in intraoperative brachytherapy, which exceeds 1000 patients, has also demonstrated improved local control, even in advanced stage of tumor but, as was to be expected, only modest survival advantage due to the high rate of distant failures in these patients. In limited stage disease, however, favorable long-term results have been achieved and suggested the efficacy of this alternative treatment option for patients with limited pulmonary reserve, without increase in late pulmonary morbidity (171. Further investigations and a longer follow-up time will be necessary to evaluate the validity of IORT combined with EBR as a treatment modali-
ty for lung cancer. Special attention will have to be directed to possible severe side effects occurring in late follow-up.
References 1 Abe, M. Intraoperative radiotherapy - past, present and future. Int. J. Radiat. Oncol. Biol. Phys. 10: 1987-1999, 1984. 2 Abe, M. and Takahashi, M. Intraoperative radiotherapy: The Japanese experience. Int. J. Radiat. Oncol. Biol. Phys. 71: 863-868, 1981. 3 Abe, M., Takahashi, M., Ono, K., Tobe, T. and Inamoto, T. Japan gastric trials in intraoperative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 15: 1431-1433,1988. 4 Abe, M., Takahashi, M., Yabumoto, E., Adachi, H., Yoshii, M. and Mori, K. Clinical experiences with intraoperative radiotherapy of locally advanced cancers. Cancer 45: 40-48, 1980. 5 Abe, M., Yabumoto, E., Nishidai, T. and Takahashi, M. Trials of new forms of radiotherapy for advanced bronchogenic carcinoma. Strahlenther. Onkol. 153: 149-158, 1977. 6 Calvo, F. A., Henriquez, J., Santos, M., Escudel, L., Ortiz de Urbina, D., Hernandez, J. L., Zornova, G., Ahenke, A. and Voltas, J. Intraoperative and external beam radiotherapy in advanced resectable gastric cancer: technical description and preliminary results. Int. J. Radiat. Oncol. Biol. Phys. 17: 183-189, 1989. 7 Calvo, F. A., Santos, M., Escude, L. and Ortiz de Urbina, D. Intraoperative radiotherapy (1984-1988): experience at the University Clinic of Navarra, Spain (Abstract). Strahlenther. Onkol. 11: 785, 1989. 8 Barnes, M., Pass, H., DeLuca, A., Tochner, Z., Potter, D., Terrill, R., Sindelar, W. F. and Kinsella, T. Response .of mediastinal and thoracic viscera of the dog to intraoperative radiation therapy (IORT). Int. J. Radiat. Oncol. Biol. Phys. 13: 371-378, 1987. 9 Cox, J. D., Byhardt, R. W. and Komaki, R. The role of radiotherapy in squamous, large cell, and adenocarcinoma of the lung. Semin. Oncol. 10: 81-94, 1983. 10 Denck, H. and Kutschera, W. Das Bronchuskarzinom aus chirurgischer Sicht. Onkologie 7: 263-266, 1984. a 1 Goldson, A. L. Past, present and prospects of intraoperative radiotherapy (IOR). Semin. Oncol. 8: 59-64, 1981. 12 Gross, N. J. Pulmonary effects of radiation therapy. Ann. Intern. Med. 86: 91-92, 1977. 13 Gunderson, L. L., Cohen, A. C., Dosoretz, D. D., Shipley, W. V., Hedberg, S. E., Wood, W. C., Rodkey, G. V. and Siut, H. D. Residual, unresectable, or recurrent colorectal cancer: external beam irradiation and
144
14
15
16
17
18
19
20
21
22
23
intraoperative electron boost + resection. Int. J. Radiat. Oncol. Biol. Phys. 9: 1597-1606, 1983. Gunderson, L. L., Martin, J. K., Beart, R. W., Nagorney, D. M., Fieck, J., Wieand, H. S., Martinez, A., O’Conell, M. J. and Martensen, J. A. External beam and intraoperative electron beam irradiation for colorectal cancer. Int. J: Radiat. Oncol. Biol. Phys. (Suppl.) 12: 147, 1986. Gunderson, L. L., Shipley, W. U., Suit, H. D., Epp, E. R., Nardi, G., Wood, W., Cohen, A., Nelson, J., Battit, G., Biggs, P., Russel, A., Rockett, A. and Clark, D. Intraoperative radiation. Cancer 49: 2259-2266, 1982. Haffty, B. G., Goldberg, N. B., Gerstley, J., Fischer, D. B. and Peschel, R. Results of radical radiation therapy in clinical stage I technically operable non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15: 69-73, 1988. Hilaris,.B. S. and Martini, N. The current state of intraoperative interstitial brachytherapy in lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15: 1347-1354, 1988. Hoekstra, H. J., Sindelar, W. F. and Kinsella, T. J. Surgery with intraoperative radiotherapy for sarcomas of the pelvic girdle: A pilot experience. Int. J. Radiat. Oncol. Biol. Phys. 15: 1013-1016, 1988. Katz, H. R. and Alberts, R. W. A comparison of high dose continuous and split course irradiation in non-oatcell carcinoma ofthe lung. Am. J. Clin. Oncol. 6: 445-457, 1983. Leitner, H., Arian-Schad, K., Hackl, A., Jiittner, F., Kohek, P. and Friehs, G. Technical and physical aspects of intraoperative radiation therapy. In: Progress in Radio-Oncology IV, pp. 237-240. Editors: K. H. Karcher, H. D. Kogelnik, B. Stadler and T. Szepesi. International Club for Radio-Oncology, Austria, Vienna, 1988. McCormack, P.M. and Martini, N. Primary lung cancer: results with conservative resection in treatment. N.Y. Stat. J. Med. 80: 612-616, 1980. Mountain, C. F. Assessment of the role of surgery for the control of lung cancer. Ann. Thorac. Surg. 24: 365-373, 1977. Mountain, C. F. Biologic, physiologic and technical de-
24
25
26
27
28
29
30
31
terminants in surgical therapy of lung cancer. In: Lung Cancer: Clinical diagnosis and treatment, pp. 158-198. Editor: M. F. Straus. Grune and Stratton, New York, 1977. Noordjik, E. M., Poest Clement, E. v. d., Hermans, J., Wever, A. M. J. and Leer, J. W. H. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother. Oncol. 13: 83-89, 1988. Pass, H. I., Sindelar, W. F., DeLuca, A. M., Barnes, M., Kutzmann, S., Hoekstra, H., Tochner, Z., Roth, J. and Glatstein, E. Delivery of intraoperative radiation therapy after pneumectomy: experimental observations and early clinical results. Ann. Thorac. Surg. 44: 14-20, 1987. Perez, C. A., Stanley, K., Grundy, G., Hanson, W., Rubin, P., Kramer, S., Brady, L., Marks, J., PerezTomayo, R., Brown, S., Concannon, J. and Rothmann, M. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat-cell carcinoma of the lung. Report by the Radiation Therapy Oncology Group. Cancer 50: 1091-1099, 1982. Rich, T. Radiation therapy for pancreatic cancer: eleven year experience at the JCRT. Int. J. Radiat. Oncol. Biol. Phys. 11: 759-763, 1985. Sindelar, W. F., Hoekstra, H. J. and Kinsella, T. J. Surgical approaches and technique in intraoperative radiotherapy for intra-abdominal, retroperitoneal, and pelvic neoplasms. Surgery 103: 247-256, 1988. Sindelar, W. F., Hoekstra, H. J., Kinsella, T. J., Barnes, M., DeLuca, A. M., Tochner, Z., Pass, H. I., Kranda, K. C. and Terrill, R. E. Response ofcanine esophagus to intraoperative electron beam radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 15: 663-669, 1988. Stanley, K., Cox, J. D., Petrovic, Z., and Paig, C. Patterns of failure in patients with inoperable carcinoma of the lung. Cancer 47: 2725-2729, 1981. Williams, D. E., Pairolebo, P., Davis, C., Bernatz, P., Payne, W., Taylor, W., Uhlenhopp, M. and Fontana, R. Survival of patients surgically treated for stage I lung cancer. J. Thorac. Cardiovas. Surg. 82: 70-76, 1981.
137
RADION 00769
Intraoperative plus external beam irradiation in nonresectable lung cancer: assessment of local response and therapy-related side effects Karin S. Arian-Schad I, Freyja M. Juettner 2, Beatrix Ratzenhofer 3, Hubert Leitner ‘, Guenter Porsch I, Hans Pinter *, Franz Ebner I, Arnulf G. Hack1 ’ and Gerhard B. Friehs * University Clinic of Radiology.
’Division of Radiotherapy, Departments of 2 Thoracic and Hyperbaric Surgery, and 3 Department of Anesthesiology, University Medical School Graz, Graz, Austria
(Received 8 January 1990, revision received 3 May 1990, accepted 10 May 1990)
Ke_Jawords
: Intraoperative radiation; External beam therapy; Lung cancer
Summary
(NSCLC), stage T,_, N,_, M,, have undergone lymph node dissection and intraoperative radiation therapy (IORT) to the primary with Since
1987, 24 patients
with inoperable
non-small-cell
lung cancer
lo-20 Gy. Patient selection criteria were nonresectability based on severe cardiorespiratory impairment, no radiological evidence of distant metastases and a Karnofsky performance status of > 80. In 18 patients the IORT procedure was followed by an external beam radiation series (EBR) including the tumor with 46 Gy and the regional lymph nodes with 46/56 Gy. The tumor response was assessed by CAT-scan volumetry before the institution of IORT, 4 weeks later, before the onset of EBR, 8 weeks after the combined treatment course and on a 3 months basis thereafter. Prospectively, MRI of the thorax with/without Gadolinium-DTPA was performed to examine contrast enhancement and signal behavior of the tumor, in an attempt to differentiate residual disease compared to therapy-related collateral damage. So far, 18 patients have completed the combined treatment course with a median follow-up of 11 months (range 4.5 to 25 months). The overall local response rate (CR and PR) was 88.2%. In detail, 11 complete responses, 6 partial responses and one minimal response were observed. The overall and recurrence-free survival at 25 months was 49.6% and 83.3%, respectively.
Introduction Cancer of the lung is the leading cause of death in the male population in the western industrial Address for correspondence
: Karin S. Arian-Schad, UniverClinic of Radiology, Division of Radiotherapy, Auenbruggerplatz 9, A-8036 Graz, Austria. sity
world. Although radical surgery offers a good chance for cure in limited stage of disease [ 10,21-23,311, 70% of patients will be found unsuitable for oneration at time of diagnosis [ 9,22,23]. Due td either severe cardioresp;atory impairment, which surgical procedure,
0167-8140/90/$03.50 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)
does not allow an extensive or to anatomical unresecta-
138 bility and/or distant spread, these patients ultimately might be considered to receive radiation treatment during their course of disease [9,16,24,26]. Various doses of radiation and fractionation schedules have been used in patients with bronchogenic carcinoma [ 16,19,26,30]. Several studies have indicated, that the probability of local control depends on the total dose delivered, but even with high doses, up to 44% of patients showed failure at the initial site of the tumor. Only patients in whom local control had been achieved had a prolonged survival [26,30]. Sensitive structures and normal lung parenchyma within the treatment field restrict further increase in dosage in spite of sophisticated treatment planning methods. This is particulary relevant in patients, in whom cardiopulmonary dysfunction is the cause for inoperability, or in patients, in whom large portals would be required to encompass the lesion and the regional area of lymphatic spread
We did a controlled study, applying IORT in combination with postoperative EBR in a collective of functionally nonresectable patients, who otherwise would have been candidates for conventional EBR only. In order to assess the treatment response and possible side effects in this patient series, short term follow-up examinations with CAT-scan were scheduled. As the study was ongoing, native and contrast MRI was used in addition to obtain further information in differentiating collateral damage and tumor regression.
Patients and methods Between October 1987 and November 1989, 24 patients (3 females, 2 1 males), aged 5 l-80 years (mean: 65 years) were treated with IORT to the unresected primary. Treatment selection criteria included patients with histopathologically or cytologically confirmed diagnosis of non-small-cell
[121. Intraoperative radiation therapy (IORT) has demonstrated to be a feasible approach for tumors, in which, due to their topographical location, doses necessary for local control cannot be delivered safely by external treatment alone [l-4,1 1,15,18,27,28]. In addition, IORT has been demonstrated to be an attractive boosting modality in conjunction with surgery and/or conventional external beam radiation for a variety of tumors [3,6,11,13-14,271. The clinical experience of IORT in lung cancer is still limited [ 1,4,5,7,11,25]. Several experimental studies have evaluated the tolerance of mediastinal structures and/or lung tissue to large single dose radiation delivered intraoperatively :[ 8,25,29]. Information on lung tolerance to external beam radiation (EBR) given in addition to IORT is scarce [ 71. No data exist concerning acute or late tissue reactions following a combined IORT/EBR approach or on the difficulties encountered in obtaining follow-up evaluation, which can differentiate residual disease from marked fibrosis related to normal tissue damage.
TABLE
I
Patient pretreatment
characteristics.
No. of patients Tumor stage (AJC) T,
24 7
T,
10
T,
7
Lymph node involvement NO
15
N,
2
N*
7
Histologic subtype
Squamous Adeno Large cell
14 6 4
Tumor grading
Moderately differentiated Poorly differentiated
13 11
Localisation
Left upper lobe Left lower lobe Right upper lobe Right lower lobe
6 5 4 9
139 lung cancer (NSCLC), stage T,_, N,_, (AJC staging criteria 1988) and no radiological evidence of distant metastases (Table I). Only cases, who were considered inoperable because of severe cardiopulmonary impairment with a Karnofsky performance status of > 80 entered this protocol. Pretreatment evaluation included history, physical examination, blood chemistries, chest X-ray, CT and MRI of the thorax, fibrebronchoscopy and cardiorespiratory function tests (spirometry, ventilation-perfusion body-plethysmography, exercise electrocardiogram, scan, ergometry, ultrasound cardiography). In addition, bone scan and ultrasound of the abdomen were performed to help rule out distant metastases. Prospectively, an external photon beam series (8 MeV) to the tumor with 46 Gy and the regional lymph nodes with 46/56 Gy was scheduled 4 weeks after IORT with curative intention. Surgical technique and IORT Surgery is performed inside the radiation therapy room under sterile conditions. The tumor is exposed by a posterolateral thoracotomy and a biopsy is taken by pulmotomy in cases in whom only cytological diagnosis had been obtained. Lymph node dissection in the respective drainage area, following the standard procedure otherwise combined with resection, is done for staging purposes. Both the tumor biopsy and the dissected lymph nodes are examined intraoperatively by frozen section histology before IORT is initiated. Because of the poor cardiorespiratory function in our collective, IORT had to be delivered with the tumor-bearing lung partially ventilated. This technique provided both satisfactory ventilation and sufficient mobility of tumor-bearing lung at its hilum which is necessary for an optimum positioning of the cone. Dependent on the tumor size of the primary a lucite sterile cone of appropriate diameter is firmly put over the lesion with a macroscopically tumorfree margin of 1.5 cm. Doses between 10 and 20 Gy, with electron energies in the range of 11 to 20 MeV are applied to ensure homogeneous dose
TABLE
II
IORT treatment
data of 24 patients
IORT tumor dosage (Gy) (90 % isodose) 10
15 11 20
1 2 1 20
Electron beam energy (MeV) I
1
11
6
15
13
20
4
Cone diameter (cm) 4
1
6
12
8
6
10
5
distribution within the treatment volume (Table II). Dose-limiting structures are simultaneously shielded. by 2 cm thick aluminum blocks, which are positioned between the tumor and underlying or adjacent normal tissue. This is to ensure additional protection of structures known for sensitivity, such as esophagus, trachea, heart, spinal cord and big vessels. The IORT set-up, consisting of straight and beveled cones with diameters of 4- 10 cm, and the adaptor system with a secondary collimator connected to the accelerator head, are both selfdeveloped [20]. Since calibration of the accelerator beam is done on a day to day basis, the dose calculation data for the various cone diameters and energies prescribed to the 90% iso-dose, are listed in a table and thus allow quick determination of dosimetry parameters. Special protocol forms are used for documentation of clinical and physical data of the IORT procedure. External beam radiation Four weeks after IORT an external photon beam (8 MeV) radiation series with conventional fractionation (2 Gy/day, 5 times a week) is initiated. Treatment is planned with a CT-aided
140 computer planning system with dose calculation in at least three section planes. Radiation is delivered through individually shaped divergent cerrobend blocks using AP/PA fields and additional lateral fields in patients with left lower lobe tumors, in order to reduce the dosage to the heart. A total dose of 46 Gy is applied to the tumor and the regional lymph node area. In patients with histopathologically confirmed lymph node involvement an additional electron boost to the mediastinum is added to increase the total dose up to 56 Gy. For the mediastinal boost electron energies of either 20 or 25 MeV are used in order to ensure a homogeneous dose distribution in the target volume. For an optimum delivery precluding damage to the spinal cord, computerized treatment planning is performed in each case. Radiologicalfollow-up Follow-up consisted of CAT-scan volumetry of the tumor preoperatively, 4 weeks after IORT, 8 weeks after IORT and EBR, and on a 3 months basis thereafter. Additional 4 mm scans in a high resolution mode were performed, to assess possible interstitial changes of the lung parenchyma within the intraoperative treatment port. Since 1988, MRI with and without Gadolinium-DTPA contrast medium has been utilized to examine the contrast behavior of the tumor before and after radiation therapy. Patients were examined with a 1.5 Tesla Gyroscan (Tlweighted spin-echo sequences, repetition times of 550-750 ms, echo times 25-30 ms) in at least two planes, followed by contrast scans after intravenous injection of 0.1 mmol Gd-DTPA/kg.
Results Eighteen of 24 patients have so far undergone the combined IORT/EBR approach and are available for evaluation of tumor response (Fig. 1) with a median follow-up time of 11 months (range 4.5 to 26 months).
Volume
of turnour (am31
Patients ranked according to intial vol. 0
VoIum*try
4
es
VOIUm*try
vohJm*try
1
I
Pr*alr*atm.
Volunntry
3
2
Volum*
Fig. 1. Pre- and post-therapeutic tumor volume measurements in 18 patients treated with IORT and EBR.
The first follow-up volumetry, 4 weeks after IORT, revealed 9 minimal responses (MR, tumor regression 50%), and one complete response (CR). In one patient volume regression could not be assessed due to marked surgically and/or radiation-induced artefacts. At second CAT-scan volumetry, 18 weeks alter IORT, 5 CR, 11 PR and 1 MR were observed, respectively. One patient was lost with a lethal intrabronchial bleeding during his course of EBR. As follow-up time reached 30-46 weeks, volume measurements were hampered by increasing tissue reactions. Furthermore, differentiation of fibrosis versus possible residual disease by CT was not reliable due to similar attenuation values of both tissues. At that time, MRI, which had been prospectively scheduled in 12 patients, seemed helpful in discerning surgically and radiation-induced parenchymal damage versus residual disease or tumor regrowth. Pleural thickening could be clearly delineated in 7/12, partial or total atelectasis in 4/12 and fibrosis in lo/12 patients, showing homogeneous signal behavior patterns with/without application of contrast medium. These findings were in contrast to focal Gd-DTPA enhancement, suspicious for residual disease, within areas of consolidation in two patients, of whom in one subsequent local
141 IORT in NSCLC (N=lS) Overall and recurrence-free
survival
20:
OrA
3
7
10 11
15
25
months -
OvBrallw.
-
recurrencstree 8”.
Fig. 2. Overall and recurrence-free EBR.
survival after IORT and
progression occurred 12 months after IORT. In one case an ipsi- and contralateral lung metastasis, both located outside the radiation ports, were diagnosed by CT and MRI, presenting with identical Gd-DTPA contrast enhancement as compared to the primary lesion before initiation of therapy. Six patients died, of which 4 succumbed to their pre-existent cardiac insulhciency 6, 12, 14 and 15 months alter IORT, including 2 patients with complete tumor regression. Only in one patient local tumor regrowth occurred with subsequent distant spread in his later course of disease. One patient died of acute intrabronchial hemorrhage while undergoing EBR. Based on both MRI findings and CT volumetries at the most recent follow-up according to the agreed schedule, an overall local control rate of 88.2% was achieved, including 11 CR and 6 PR. 16 out of the 18 patients remained without local or distant recurrence during follow-up. The overall and recurrence-free survival (Fig. 2) at 25 months was 49.6% and 83.3x, respectively.
Complications and toxicity The IORT procedure was well tolerated. Postoperative or infectious complications due to thoracotomy and lymph node dissection were not
observed. In one patient with severe bullous emphysema, a prolonged bronchopleural fistula after fine needle aspiration cytology, necessitated an intercostal suction drainage for 10 days. In another case, the hospital stay was prolonged due to cerebrovascular insufficiency. The median duration of hospital care after IORT was 10.7 days. One serious complication, which might have been associated to IORT, occurred in a patient, in whom a cavitating lesion and infiltration into the pulmonary vein had been diagnosed before initiation of therapy. After 50% of tumor regression he died of intrabronchial hemorrhage during his course of EBR. One patient presented with unexplained transient thrombocytopenia (20000 cm3 platelets) 2 weeks after IORT. Paraneoplastic symptoms limited to the skin were observed in three cases, including dermatalgia, pruritus and one erythema multiforme (Table III). These reactions were noted at a median time of 4 months after completion of therapy and affected two patients with clinically complete remission of tumor. Pronounced pneumonitis causing clinical symptoms occurred in five patients, starting 16-18 weeks after IORT, whereas radiological signs of acute parenchymal reactions were observed as early as 4 weeks in one patient and 10 weeks after IORT in two patients. In the remaining cases, however, pneumonitis causing clinical symptoms, was clearly related to marked parenchymal changes within the external radiation ports. The onset and duration of these acute reactions was comparable to acute side
TABLE
III
Complications
and toxicity.
Prolonged fistula after fine needle aspiration cytology Intrabronchial hemorrhage Thrombocytopenia Pneumonitis with clinical symptoms Paraneoplastic pruritus Paraneoplastic dermatalgia Erythema multiforme
1 1 1 5 1 1 1
142 effects associated with EBR alone. An increase in acute lung tissue damage within IORT portals could not be observed, which might have been due to a “miss”, simply by overlapping of IORT and EBR-induced tissue reactions. In all patients the external series could be delivered on an outpatient basis. The common side effects of EBR, such as fatigue, loss of appetite, tracheitis and esophagitis did not seem to be enhanced by the combined treatment regimen. All patients were able to resume their normal life within 2 months after completion of therapy. Late side effects, other than fibrotic changes of varying extent within external treatment portals, could not be observed up to this time.
Discussion The curative role of surgery in technically operable lung cancer is well established [ 10,22,23,3 I]. The comparison of surgical and radiation therapy series, however, remains crucial, since intraoperative staging can hardly be compared to a radiological one, in spite of modern imaging techniques. In recent years, the curative efficacy of aggressive radiotherapy has been investigated and several studies indicated, that increase in dosage yields a higher probability of intrathoracic tumor control and improves survival. In fact, a series by Noordjik et al. [24] reported on a 5-year survival of 42 y0 in a group of primarily irradiated patients with stage T,_, N, M, tumors, who had achieved a complete response to therapy. These results compared favorably to a group of patients, who under the same circumstances were selected for operation. The correlation between dose and objective tumor response has been clearly demonstrated by the RTOG study, with local failure rates of 48% in patients treated with 40 Gy as compared to 27% in those who received 60 Gy continuous course treatment [26]. This study comprised a high percentage of advanced lesions and also showed that doses of 60 Gy still are insufficient for tumors which exceed 6 cm in diameter.
With further increase of dosage, however, irreversible damage to surrounding tissue is to be expected, in spite of shrinking field technique, based upon sophisticated treatment planning. Theoretically, the use of IORT may thus improve the therapeutic ratio between tumor control and normal tissue toxicity, and permits the delivery of adequate tumor doses with maximum sparing of normal lung parenchyma. Some authors, such as Abe et al. [ 1,2] have pointed out that many patients with carcinoma of the lung die with distant metastases, and thus represent poor candidates for IORT. It has to be kept in mind, however, that survival is not a reliable indicator of effectiveness of irradiation in tumors, which are known to have a high tendency for systemic spread and in whom chemotherapy usually fails to alter the course of disease. In absence of distant metastases at initiation of treatment, and in cases of posttherapeutic control of tumor, an improvement of long-term survival can be expected in at least one third of patients. In our protocol, which was primarily inducted for functionally inoperable patients, nine cases turned out be technically unresectable as well. In seven, lymph node dissection revealed involvement of N, nodes, which were resected as radically as possible and treated with 56 Gy external radiation. None of these patients, up to now, has failed in the mediastinum and only one patient with N, nodes has so far developed distant metastases 16 months after treatment alongside local regrowth of the primary. In comparison to other studies [ 16,26,30], the intrathoracic failure rate of 11% at 2 years, including the patient with subsequent developement of intrapulmonary metastases, is comparatively low. The overall local response rate of 88.2% (CR and PR), with 6 1 y0 complete remissions based on CT and MRI evaluation seems promising. Taking into account the poor general medical condition of our patients, which was, after all, the reason for nonresectability, thoracotomy with IORT and EBR was extremely well tolerated. Even though follow-up is limited, the preliminary results with an overall survival (four intercurrent
143 deaths included) of 49.6% and a recurrence-free survival of 83.3%, are encouraging. A local response rate of 80% in 30 patients has been reported by Calvo et al. [7], utilizing a similar treatment approach. In his series, however, IORT was also applied in radically or partially resected lesions and thus cannot be strictly compared to our study. The low complication rate in our patients might be based upon careful avoidance of mediastinal structures into the IORT port, the additional shielding of adjacent sensitive structures and the fact that IORT doses have been limited to lo-20 Gy, depending on tumor size and location. Experimental data by Pass et al. [25] and Barnes et al. [8], as well as early clinical results have demonstrated, that irradiation of mediastinal structures with doses in excess of 20 Gy might result in severe damage and life-threatening symptoms. Goldson [ 111 reported on four cases treated by IORT of the hilum after the primary had been resected. In one patient, who died 6 months after treatment, esophageal stricture was found. The largest series on 5 1 patients with intrathoracic malignancies treated with IORT was reported by Abe et al. [ 21. Detailed data are given in eight patients, of whom only one patient received additional EBR. The median survival time in these patients with far advanced disease was 9 months, with 5 of 8 patients succumbing to their disease within the first year [4]. The Memorial Sloan-Kettering Cancer Center experience in intraoperative brachytherapy, which exceeds 1000 patients, has also demonstrated improved local control, even in advanced stage of tumor but, as was to be expected, only modest survival advantage due to the high rate of distant failures in these patients. In limited stage disease, however, favorable long-term results have been achieved and suggested the efficacy of this alternative treatment option for patients with limited pulmonary reserve, without increase in late pulmonary morbidity (171. Further investigations and a longer follow-up time will be necessary to evaluate the validity of IORT combined with EBR as a treatment modali-
ty for lung cancer. Special attention will have to be directed to possible severe side effects occurring in late follow-up.
References 1 Abe, M. Intraoperative radiotherapy - past, present and future. Int. J. Radiat. Oncol. Biol. Phys. 10: 1987-1999, 1984. 2 Abe, M. and Takahashi, M. Intraoperative radiotherapy: The Japanese experience. Int. J. Radiat. Oncol. Biol. Phys. 71: 863-868, 1981. 3 Abe, M., Takahashi, M., Ono, K., Tobe, T. and Inamoto, T. Japan gastric trials in intraoperative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 15: 1431-1433,1988. 4 Abe, M., Takahashi, M., Yabumoto, E., Adachi, H., Yoshii, M. and Mori, K. Clinical experiences with intraoperative radiotherapy of locally advanced cancers. Cancer 45: 40-48, 1980. 5 Abe, M., Yabumoto, E., Nishidai, T. and Takahashi, M. Trials of new forms of radiotherapy for advanced bronchogenic carcinoma. Strahlenther. Onkol. 153: 149-158, 1977. 6 Calvo, F. A., Henriquez, J., Santos, M., Escudel, L., Ortiz de Urbina, D., Hernandez, J. L., Zornova, G., Ahenke, A. and Voltas, J. Intraoperative and external beam radiotherapy in advanced resectable gastric cancer: technical description and preliminary results. Int. J. Radiat. Oncol. Biol. Phys. 17: 183-189, 1989. 7 Calvo, F. A., Santos, M., Escude, L. and Ortiz de Urbina, D. Intraoperative radiotherapy (1984-1988): experience at the University Clinic of Navarra, Spain (Abstract). Strahlenther. Onkol. 11: 785, 1989. 8 Barnes, M., Pass, H., DeLuca, A., Tochner, Z., Potter, D., Terrill, R., Sindelar, W. F. and Kinsella, T. Response .of mediastinal and thoracic viscera of the dog to intraoperative radiation therapy (IORT). Int. J. Radiat. Oncol. Biol. Phys. 13: 371-378, 1987. 9 Cox, J. D., Byhardt, R. W. and Komaki, R. The role of radiotherapy in squamous, large cell, and adenocarcinoma of the lung. Semin. Oncol. 10: 81-94, 1983. 10 Denck, H. and Kutschera, W. Das Bronchuskarzinom aus chirurgischer Sicht. Onkologie 7: 263-266, 1984. a 1 Goldson, A. L. Past, present and prospects of intraoperative radiotherapy (IOR). Semin. Oncol. 8: 59-64, 1981. 12 Gross, N. J. Pulmonary effects of radiation therapy. Ann. Intern. Med. 86: 91-92, 1977. 13 Gunderson, L. L., Cohen, A. C., Dosoretz, D. D., Shipley, W. V., Hedberg, S. E., Wood, W. C., Rodkey, G. V. and Siut, H. D. Residual, unresectable, or recurrent colorectal cancer: external beam irradiation and
144
14
15
16
17
18
19
20
21
22
23
intraoperative electron boost + resection. Int. J. Radiat. Oncol. Biol. Phys. 9: 1597-1606, 1983. Gunderson, L. L., Martin, J. K., Beart, R. W., Nagorney, D. M., Fieck, J., Wieand, H. S., Martinez, A., O’Conell, M. J. and Martensen, J. A. External beam and intraoperative electron beam irradiation for colorectal cancer. Int. J: Radiat. Oncol. Biol. Phys. (Suppl.) 12: 147, 1986. Gunderson, L. L., Shipley, W. U., Suit, H. D., Epp, E. R., Nardi, G., Wood, W., Cohen, A., Nelson, J., Battit, G., Biggs, P., Russel, A., Rockett, A. and Clark, D. Intraoperative radiation. Cancer 49: 2259-2266, 1982. Haffty, B. G., Goldberg, N. B., Gerstley, J., Fischer, D. B. and Peschel, R. Results of radical radiation therapy in clinical stage I technically operable non-small cell lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15: 69-73, 1988. Hilaris,.B. S. and Martini, N. The current state of intraoperative interstitial brachytherapy in lung cancer. Int. J. Radiat. Oncol. Biol. Phys. 15: 1347-1354, 1988. Hoekstra, H. J., Sindelar, W. F. and Kinsella, T. J. Surgery with intraoperative radiotherapy for sarcomas of the pelvic girdle: A pilot experience. Int. J. Radiat. Oncol. Biol. Phys. 15: 1013-1016, 1988. Katz, H. R. and Alberts, R. W. A comparison of high dose continuous and split course irradiation in non-oatcell carcinoma ofthe lung. Am. J. Clin. Oncol. 6: 445-457, 1983. Leitner, H., Arian-Schad, K., Hackl, A., Jiittner, F., Kohek, P. and Friehs, G. Technical and physical aspects of intraoperative radiation therapy. In: Progress in Radio-Oncology IV, pp. 237-240. Editors: K. H. Karcher, H. D. Kogelnik, B. Stadler and T. Szepesi. International Club for Radio-Oncology, Austria, Vienna, 1988. McCormack, P.M. and Martini, N. Primary lung cancer: results with conservative resection in treatment. N.Y. Stat. J. Med. 80: 612-616, 1980. Mountain, C. F. Assessment of the role of surgery for the control of lung cancer. Ann. Thorac. Surg. 24: 365-373, 1977. Mountain, C. F. Biologic, physiologic and technical de-
24
25
26
27
28
29
30
31
terminants in surgical therapy of lung cancer. In: Lung Cancer: Clinical diagnosis and treatment, pp. 158-198. Editor: M. F. Straus. Grune and Stratton, New York, 1977. Noordjik, E. M., Poest Clement, E. v. d., Hermans, J., Wever, A. M. J. and Leer, J. W. H. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother. Oncol. 13: 83-89, 1988. Pass, H. I., Sindelar, W. F., DeLuca, A. M., Barnes, M., Kutzmann, S., Hoekstra, H., Tochner, Z., Roth, J. and Glatstein, E. Delivery of intraoperative radiation therapy after pneumectomy: experimental observations and early clinical results. Ann. Thorac. Surg. 44: 14-20, 1987. Perez, C. A., Stanley, K., Grundy, G., Hanson, W., Rubin, P., Kramer, S., Brady, L., Marks, J., PerezTomayo, R., Brown, S., Concannon, J. and Rothmann, M. Impact of irradiation technique and tumor extent in tumor control and survival of patients with unresectable non-oat-cell carcinoma of the lung. Report by the Radiation Therapy Oncology Group. Cancer 50: 1091-1099, 1982. Rich, T. Radiation therapy for pancreatic cancer: eleven year experience at the JCRT. Int. J. Radiat. Oncol. Biol. Phys. 11: 759-763, 1985. Sindelar, W. F., Hoekstra, H. J. and Kinsella, T. J. Surgical approaches and technique in intraoperative radiotherapy for intra-abdominal, retroperitoneal, and pelvic neoplasms. Surgery 103: 247-256, 1988. Sindelar, W. F., Hoekstra, H. J., Kinsella, T. J., Barnes, M., DeLuca, A. M., Tochner, Z., Pass, H. I., Kranda, K. C. and Terrill, R. E. Response ofcanine esophagus to intraoperative electron beam radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 15: 663-669, 1988. Stanley, K., Cox, J. D., Petrovic, Z., and Paig, C. Patterns of failure in patients with inoperable carcinoma of the lung. Cancer 47: 2725-2729, 1981. Williams, D. E., Pairolebo, P., Davis, C., Bernatz, P., Payne, W., Taylor, W., Uhlenhopp, M. and Fontana, R. Survival of patients surgically treated for stage I lung cancer. J. Thorac. Cardiovas. Surg. 82: 70-76, 1981.
